Is vitamin D status relevant to psoriasis and psoriatic arthritis? A retrospective cross-sectional study

Abstract BACKGROUND: Psoriasis is a systemic, immune-mediated disease characterized by inflammatory manifestations in the skin and joints. Vitamin D deficiency is currently considered a pandemic and is associated with comorbidities including psoriasis and psoriatic arthritis (PsA). OBJECTIVES: To determine the prevalence of hypovitaminosis D [25(OH)D] in patients with plaque psoriasis, with and without PsA, and of independent predictors of serum 25(OH)D levels. DESIGN AND SETTING: Retrospective cross-sectional study conducted among 300 patients at an outpatient clinic in a university center in Juiz de Fora, Minas Gerais, Brazil. METHODS: Demographic and clinical data (psoriasis area and severity index [PASI], family history, age at onset, disease duration, and the presence of PsA according to Classification Criteria for Psoriatic Arthritis), skin phototype, and season of the year were reviewed. RESULTS: Hypovitaminosis D (< 30 ng/mL) was highly prevalent in patients with psoriasis with and without PsA (82.2% and 74.9%, respectively). An inverse correlation between PASI and vitamin D was found (without PsA r = –0.59 and, PsA r = –0.52, P < 0.001), and multivariate regression revealed that hypovitaminosis D was associated with disease severity, season, and phototype. It was confirmed by binary logistic regression between PASI and vitamin D deficiency (< 30 ng/mL), (odds ratio, OR 1.78 CI: –0.20–0.53, P < 0.001). CONCLUSION: Hypovitaminosis D (< 30 ng/mL) was highly prevalent in psoriatic patients with and without PsA. Season and skin phototype were associated with 25(OH)D levels. An inverse association between PASI and serum 25(OH)D levels was established.


INTRODUCTION
Psoriasis is a chronic disease with a genetic predisposition. It involves the skin, joints, and immune system, 1 and is characterized by sustained inflammation with alterations in the proliferation and differentiation of keratinocytes. 2 The pathogenesis of psoriasis is still not completely understood. However, it is already known that the development of psoriasis plaques is mediated by Th1, Th17, and Th22 cells, with consequent hyperproliferation of keratinocytes. 2 Vitamin D is considered one of the most important modulators of the immune response, with effects on both innate and adaptive immunity in addition to having antiproliferative actions on keratinocytes. 2,3 Moreover, beneficial effects of ultraviolet radiation in the treatment of psoriasis reinforce this hypothesis. [2][3][4] The role of vitamin D in psoriasis has been studied for over 60 years, since vitamin D analogs, such as calcipotriol, were first used to treat psoriasis. Currently, vitamin D deficiency is considered a worldwide epidemic with multiple implications for human health because of the roles of vitamin D in various physiological systems. Vitamin D deficiency increases the risk of cardiovascular and metabolic diseases, cognitive and affective disorders, and osteoporosis.
Chronic inflammation present in patients with psoriasis and psoriatic arthritis could be related to a higher risk of metabolic syndrome and cardiovascular disease in these individuals. [4][5][6][7] The definition of vitamin D deficiency is still controversial. The Institute of Medicine (IOM) of the National Academy considers vitamin D deficiency 25(OH)D values below 20 ng/mL (or 50 nmol/L) while other societies such as Endocrine Society, National Osteoporosis Foundation, International Osteoporosis Foundation, American Geriatric Society, suggest that the minimum value necessary to reduce the risk of falls and fractures is 30 ng/mL (or 75 nmol/L). 6,7 The World Health Organization advises serum levels above 30 ng/mL (or 75 nmol/L). 8

Clinical, laboratory and radiographic evaluation
Standardized records of patients with psoriasis were used and the following variables were evaluated: sex, age, family history of psoriasis, age at disease onset, duration of the disease, presence of PsA according to CASPAR 12 , and disease severity according to the psoriasis area and severity index (PASI). 13 Using PASI, the severity of psoriasis was stratified as mild (PASI < 10) or moderate-to-severe (PASI > 10). 13  States) and considered the following parameter definitions: values < 20 ng/mL were considered deficient; ≥ 20 ng/mL and < 30 ng/mL, insufficient; and ≥ 30 ng/mL, sufficient. 14 Rheumatoid factor and radiographic reports were also reviewed.

Statistical analyses
A descriptive data analysis was performed. The Shapiro-Wilk test was used to assess the distributions of variables. Student's t-test was used to test the differences in quantitative variables between two groups and these were confirmed by one-way analysis of variance (F test), followed by the Bonferroni post hoc correction.
The chi-square test (χ 2 ), or Fisher's exact test when there were less than five data points were used to test for possible differences in the proportions of qualitative variables.
Pearson's coefficient (r) was used to test the correlations between 25(OH)D and continuous variables. To assess independent predictors of vitamin D levels, a multiple linear regression model was developed using vitamin D levels as the outcome and sex, age, phototype, season of vitamin D blood testing, arthritis, family history, age at diagnosis, duration of psoriasis, and disease severity as determinants, and controlling, if necessary, for confounding variables such as sex and age.
In this context, the presence of arthritis, severity according to PASI, family history, age at diagnosis, evolution time, phototype, and season were used as predictor variables, controlling for sex and age.
In the binary regression, vitamin D was dichotomized as deficient (< 30 ng/mL) or sufficient (≥ 30 ng/mL), and clinical parameters related to psoriasis and psoriatic arthritis were used as predictors of vitamin D levels. The significance level was set at 5%

RESULTS
The characteristics of patients with plaque psoriasis with and without arthritis are shown in Table 1 (Figure 1) Table 2).
The multivariate linear regression model is presented in Table 3 (adjusted model, R 2 = 0.31, P < 0.001). The presence of arthritis, severity according to the PASI, family history, age at diagnosis,  The 25(OH)D levels were inversely correlated with PASI values (patients without arthritis Pearson's r = -0.59, P < 0.001 and with arthritis r = -0.52, P < 0.001).
To confirm the inverse correlation between vitamin D levels and PASI scores, we developed a binary logistic regression model ( Table 4). This model confirmed a strong association between PASI and vitamin D deficiency (< 30 ng/mL) (odds ratio, OR 1.78, CI: -0.20 to -0.53, P < 0.001). Some previous studies have confirmed the association between vitamin D deficiency and psoriasis 9,10,14-18 ; however, in contrast to those studies, a few studies have shown no correlation between them. [19][20][21] There have been a few studies investigating the comparison between psoriatic patients with and without arthritis. 18,[22][23][24] In situations of low concentrations of 25(OH)D, the immune system favors the development of self-reactive T cells directed against the body's own tissues, and the synthesis of pro-inflammatory cytokines (IL-12 and IFN-γ), predisposing the body to an increased risk of developing autoimmune diseases such as diabetes, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel diseases. [25][26][27] In psoriasis, the immune system behaves similarly under low concentrations of 25(OH)D and in addition, 25(OH)D is believed to inhibit the production of Th1 and Th17 inflammatory cytokines. 28 Orgaz-Molina et al. 10 evaluated 43 white patients with plaque psoriasis, 7% of which were associated with psoriatic arthritis with a mean PASI of 4.42, and observed a strong association between psoriasis and vitamin D insufficiency according to logistic regression (< 30 ng/mL) (OR 2.89 CI 95 1.02 to 7.64). However, vitamin D deficiency was not associated with PASI, neither with disease duration nor with the presence of arthritis, which finding differs from our results. 10 A lack of correlation of vitamin D insufficiency with PASI despite a high prevalence of deficiency in psoriatic patients, was PASI was significantly higher in patients with arthritis (P < 0.001).    19 These data disagree with our study results.

DISCUSSION
This can be explained in part by the fact that our study was conducted in a place located at latitude 21 0 S 43 0 W, which theoretically would be related to adequate levels of vitamin D, and they studied   other clinical forms of psoriasis; the phototypes were lower (I and II). It is important to point out that patients with severe psoriasis, with extensive areas of involvement, tend to cover themselves to hide their lesions, which would consequently explain the lower sun exposure and production of vitamin D.
Regarding the comparison between psoriatic patients with and without arthritis: Orgaz-Molina et al. 18 compared 61 patients with psoriatic arthritis and 61 patients without psoriatic arthritis, found no correlation with disease severity, and concluded that 25(OH) D was inversely related to metabolic parameters in patients with psoriasis without arthritis. 18 However, the authors selected patients with mild disease (PASI = 4.76 ± 5.31 in the group without arthritis versus 3.66 ± 3.48 in the group with arthritis).
On the other hand, Kincse et al. 22 found a prevalence of hypovitaminosis D (< 30 ng/mL) in 63% of cases, with inverse correlations between serum vitamin D levels and psoriasis severity (PASI), and arthritis activity. 20 The influence of season and latitude on serum vitamin D levels was investigated by Touma et al. 24 who studied 302 patients with psoriatic arthritis, 201 in Toronto (43° 40' N) and 102 in Israel (32° 46' N), in summer and winter.
It was found that levels < 75 nmol/L (30 ng/mL) were 58.7% versus 57.9% in winter in Toronto versus Israel, respectively, and 58.6% versus 64.9% in summer. The authors also evaluated the effect of skin phototype and season, concluding that there were no differences in these variables in each studied group or between the two groups. They also did not find an association between PASI and arthritis activity marker levels. However, the selected individuals had lower PASI averages calculated by rheumatologists (3.59 ± 5.09 in winter and 3.44 ± 5.59 in summer).
In this context, there are reports of inadequate levels of vitamin D, even in individuals with adequate exposure to the sun, due to other related factors, such as high altitudes, obesity, and skin pigmentation. [26][27][28][29] The limitations of our study include the absence of a dietary and sun exposure survey (with time and duration of exposure), and the fact that phototypes I, II, and VI were not represented.

CONCLUSIONS
In conclusion, we emphasize that hypovitaminosis D is highly prevalent in psoriatic patients with and without psoriatic arthritis and in patients with plaque psoriasis with or without arthritis.
Furthermore, there was an inverse correlation between 25(OH)D levels and disease severity (PASI). Finally, there were associations between 25(OH)D levels and season of the year and skin phototype. These findings highlight the importance of vitamin D status in these patients and emphasize the need for its regular monitoring in addition to considering vitamin D supplementation, especially in patients with moderate to severe psoriasis, with high phototypes, and during autumn and winter months.